PB1999: ATG-010 PLUS LOW-DOSE DEXAMETHASONE (SD) IN CHINESE RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM) PATIENTS PREVIOUSLY RECEIVED CHIMERIC ANTIGEN RECEPTOR T-CELL (CAR-T)
Authors: W. Fu, Z. Xia, C. Fu, W. Chen, C. Chang, B. Fang, G. An, Y. Wei, Z. Cai, S. Gao, J. Weng, L. Chen, H. Jing, F. Li, Z. Liu, X. Chen, J. Liu, Y. Yu, A. Wang, Y. Fei, L. Qiu
Journal: HemaSphere (2022)

Background: There are limited treatment options for multiple myeloma (MM) patients who have a disease progression after CAR-T therapy. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, inhibiting exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM. MARCH study, a single arm, Phase 2, registrational study evaluating Sd in Chinese RRMM pts, achieved an overall response rate (ORR) of 29.3% (95% CI: 19.7, 40.4), rejecting the null hypothesis of the study. Given its unique and novel mechanism of action, Sd preserves anti-tumor activity regardless of specific prior therapies. In the MARCH study, encouraging activity was demonstrated in a small group of Chinese RRMM pts previously exposed to CAR-T therapy. Aims: To evaluate efficacy and safety of Sd in Chinese RRMM pts previously treated with CAR-T. Methods: The study enrolled 82 pts previously exposed and refractory to a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and last line of therapy. Among them, 10 had received lymphodepleting conditioning followed by CAR-T cell therapy before study screening. ATG-010 (80mg) plus dexamethasone (20mg) was administered orally twice weekly. Response was assessed by an independent review committee. Results: Among 10 pts, 8 were male and 2 were female. Median age was 58.5 years. Median duration from MM initial diagnosis was 5.2 years. A total of 6 pts (60.0%) had high-risk cytogenetic abnormalities, including 4 pts (40.0%) with del (17p). Three pts had baseline plasmacytoma. Five pts (50%) experienced very rapid disease progression as indicated by a median of 46.2% increase of tumor burden from screening to Cycle 1 Day 1. Patients were heavily pre-treated with a median of 9.5 prior regimens (range: 5-12), with 8 receiving more than 6 regimens. Four pts were exposed to daratumumab (triple-class exposure). ORR was 50% including 1 very good partial response and 4 partial responses. Disease control rate defined as SD and above was 70%. As of 10th Feb 2022, all pts had disease progression, 5 pts are still under survival follow-up. Median duration of response was 1.4 months (mo) (95% CI: 0.96, NE). Median progression free survival was 1.9 mo (95% CI: 0.93, 3.74). Median overall survival was not reached and estimated 12-mo OS rate was 70%. After disease progression (PD) after Sd treatment, 4 pts received CD38 antibody based regimen, 4 pts received pomalidomide based regimen, 4 pts had cytotoxic therapy, 1 pt received 2nd CAR-T therapy, and 2 pts had no chance to receive any treatment due to death after rapid PD. Of note, 1 pt received selinexor plus lenalidomide based regimen and obtained a prolonged disease control. Adverse events were consistent with those events previously reported with Sd regimen in RRMM patients. The most common grade≥3 treatment emergent adverse events (TEAEs) included anemia, thrombocytopenia, neutropenia and nausea. Most events were manageable with appropriate supportive care or dose modification. Four pts (40%) experienced TESAEs, including anemia, pneumonia, neutropenia, and upper gastrointestinal hemorrhage. There were no TEAEs leading to treatment discontinuation or death. Summary/Conclusion: Sd was able to induce an encouraging response with a manageable safety profile for a group of Chinese RRMM patients desperately needing treatment after failing CAR-T therapy. This suggests that selinexor is a highly potent anti-MM therapy and further investigation is warranted, including using selinexor in combination with other anti-MM therapies in earlier lines of treatment.